Pharmacokinetics, Safety and Efficacy of Recombinant Von Willebrand Factor (rVWF) in the Treatment of Bleeding Episodes in Von Willebrand Disease (VWD)

Baxalta

Status and phase: Completed; Phase 3

Conditions: Von Willebrand Disease

Treatments: Biological: Recombinant von Willebrand factor (rVWF); Biological: Recombinant factor VIIII (rFVIII); Drug: Placebo

Study type: Interventional

Funder types: Industry

Identifiers

NCT01410227

2010-024108-84 (EudraCT Number)

071001

Details and patient eligibility

About

The purpose of this Phase 3 study is to assess the pharmacokinetics of rVWF:rFVIII and rVWF, and to assess the safety and efficacy of rVWF:rFVIII and rVWF in the treatment of bleeding events in subjects with severe hereditary von Willebrand disease (VWD).

Enrollment: 49 patients

Sex: All

Ages: 18 to 65 years old

Volunteers: No Healthy Volunteers

Inclusion criteria

• Participant has been diagnosed with:

  1. Type 1 (Von Willebrand factor: Ristocetin cofactor activity (VWF:RCo) < 20 IU/dL) or,
  2. Type 2A (VWF:RCo < 20 IU/dL), Type 2B (as diagnosed by genotype), Type 2N (Factor VIII activity (FVIII:C) <10% and historically documented genetics), Type 2M or,
  3. Type 3 ( Von Willebrand factor antigen (VWF:Ag) ≤ 3 IU/dL) or,
  4. Severe Von Willebrand disease (VWD) with a history of requiring substitution therapy with von Willebrand factor concentrate to control bleeding

• Participant, who participates in the treatment for bleeding episodes, has had a minimum of 1 documented bleed (medical history) requiring VWF coagulation factor replacement therapy during the previous 12 months prior to enrollment.

• Participant has a Karnofsky score ≥ 60%

• Participant is at least 18 and not older than 65 years of age at enrollment

• If female of childbearing potential, participant presents with a negative pregnancy test

• Participant agrees to employ adequate birth control measures for the duration of the study

• Participant is willing and able to comply with the requirements of the protocol

Exclusion criteria

• Participant has been diagnosed with pseudo VWD or another hereditary or acquired coagulation disorder other than VWD (eg qualitative and quantitative platelet disorders or elevated PT/international normalized ratio [INR] >1.4).
• Participant has a documented history of a VWF:RCo half-life of <6 hours.
• Participant has a history or presence of a VWF inhibitor at screening.
• Participant has a history or presence of a factor VIII (FVIII) inhibitor with a titer ≥0.4 BU (by Nijmegen assay) or ≥ 0.6 BU (by Bethesda assay).
• Participant has a known hypersensitivity to any of the components of the study drugs, such as mouse or hamster proteins.
• Participant has a medical history of immunological disorders, excluding seasonal allergic rhinitis/conjunctivitis, mild asthma, food allergies or animal allergies.
• Participant has a medical history of a thromboembolic event.
• Participant is HIV positive with an absolute CD4 count <200/mm3.
• Participant has been diagnosed with cardiovascular disease (New York Heart Association [NYHA] classes 1-4.
• Participant has an acute illness (eg, influenza, flu-like syndrome, allergic rhinitis/conjunctivitis, non-seasonal asthma) at screening.
• Participant has been diagnosed with significant liver disease as evidenced by any of the following: serum alanine aminotransferase (ALT) 5 times the upper limit of normal; hypoalbuminemia; portal vein hypertension (eg, presence of otherwise unexplained splenomegaly, history of esophageal varices).
• Participant has been diagnosed with renal disease, with a serum creatinine level ≥2 mg/dL.
• In the judgment of the investigator, the participant has another clinically significant concomitant disease (eg, uncontrolled hypertension) that may pose additional risks for the participant.
• Participant has been treated with an immunomodulatory drug, excluding topical treatment (eg, ointments, nasal sprays), within 30 days prior to enrollment
• Participant is pregnant or lactating at the time of enrollment.
• Participant has participated in another clinical study involving an IP or investigational device within 30 days prior to enrollment or is scheduled to participate in another clinical study involving an investigational product or investigational device during the course of this study.
• Participant has a history of drug or alcohol abuse within the 2 years prior to enrollment.
• Participant has a progressive fatal disease and/or life expectancy of less than 3 months.
• Participant is identified by the investigator as being unable or unwilling to cooperate with study procedures.
• Participant suffers from a mental condition rendering him/her unable to understand the nature, scope and possible consequences of the study and/or evidence of an uncooperative attitude.
• Participant is in prison or compulsory detention by regulatory and/or juridical order

Trial design

Primary purpose: Treatment

Allocation: Non-Randomized

Interventional model: Crossover Assignment

Masking: None (Open label)

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49 participants in 4 patient groups

PK 80 Arm (minimum of 22 subjects with severe VWD)

Experimental group

Description:

PK assessment (80 IU/kg rVWF) + 12-month treatment period

Treatment:

Biological: Recombinant factor VIIII (rFVIII)

Biological: Recombinant von Willebrand factor (rVWF)

PK 50 Arm (14 subjects with type 3 VWD)

Experimental group

Description:

Two single-blinded PK assessments (50 IU/kg rVWF + rFVIII/placebo) + 12-month treatment period

Treatment:

Drug: Placebo

Biological: Recombinant factor VIIII (rFVIII)

Biological: Recombinant von Willebrand factor (rVWF)

PK 50 Only Arm (minimum of 7 subjects with type 3 VWD)

Experimental group

Description:

PK assessment (50 IU/kg rVWF) only, no treatment of bleeding episodes

Treatment:

Drug: Placebo

Biological: Recombinant factor VIIII (rFVIII)

Biological: Recombinant von Willebrand factor (rVWF)

Treatment Only (up to 7 subjects independent of VWD subtype)

Experimental group

Description:

Treatment of bleeding episodes for a total of 12 months

Treatment:

Biological: Recombinant factor VIIII (rFVIII)

Biological: Recombinant von Willebrand factor (rVWF)